Tachykinin antagonists

Abstract

PCT No. PCT/GB93/02213 Sec. 371 Date Apr. 27, 1995 Sec. 102(e) Date Apr. 27, 1995 PCT Filed Oct. 27, 1993 PCT Pub. No. WO94/10167 PCT Pub. Date May 11, 1994 <IMAGE> (I) Compounds of formula (I), wherein Q1 represents an aryl group; the dotted line represents an optional covalent bond; one of X and Y represents H and the other represents hydroxy or C1-6alkoxy, or X and Y together form a group =O or =NOR5 where R5 is H or C1-6alkyl; Z represents O, S or NR2, where R2 is H or C1-6alkyl; W represents a bond or a saturated or unsaturated hydrocarbon chain of 1, 2, 3, 4, 5 or 6 carbon atoms; R1 represents H or C1-6alkyl. R3 represents H, C1-6alkyl or C2-6alkenyl; R4 represents an optionally substituted phenyl group; and R6 represents a specified amino group or an optionally substituted aromatic or non-aromatic azacyclic or azabicyclic group; and salts and prodrugs are tachykinin receptor antagonists.

We claim: 
     
       1. A compound of formula (I), or a salt or prodrug thereof: ##STR10## wherein Q 1  represents unsubstituted indolyl or indolyl substituted by one or more substituents selected from carbon atom substituents of the group consisting of C 1-6  alkyl, C 2-6  alkenyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, SR a , SOR a , SO 2  R a , OR a , NR a  R b , NR a  COR b , NR a  COOR b , COOR a  or CONR a  R b  and nitrogen atom substituents of the group consisting of C 1-6  alkyl, phenyl(C 1-4  alkyl), substituted phenyl(C 1-4  alkyl) wherein the substituents are one or more carbon atom substituents, as previously defined, COOR a  or CONR a  R b , where R a  and R b  independently represent H, C 1-6  alkyl, phenyl or trifluoromethyl; the dotted line represents an optional covalent bond;   one of X and Y represents H and the other represents hydroxy or C 1-6  alkoxy, or X and Y together form a group ═O or ═NOR 5  where R 5  is H or C 1-6  alkyl;   Z represents O, S or NR 2 , where R 2  is H or C 1-6  alkyl;   W represents a bond or a saturated or unsaturated hydrocarbon chain of 1, 2, 3, 4, 5 or 6 carbon atoms;   R 1  represents H or C 1-6  alkyl;   R 3  represents H, C 1-6  alkyl or C 2-6  alkenyl;   R 4  represents phenyl optionally substituted by 1, 2, or 3 groups selected from C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR a , SR a , SOR a , NR a  R b , NR a  COR b , NR a  CO 2  R b , CO 2  R a , or CONR a  R b , where R a  and R b  independently represent H, C 1-6  alkyl, phenyl or trifluoromethyl; and   R 6  represents NR 7  R 8  (where R 7  and R 8  each independently represent H, C 1-6  alkyl, phenyl optionally substituted by one or more of C 1-6  alkyl, C 1-6  alkoxy, halo or trifluoromethyl or phenylC 1-4  alkyl optionally substituted in the phenyl ring by one or more of C 1-6  alkyl, C 1-6  alkoxy, halo or trifluoromethyl) or an optionally substituted aromatic or non-aromatic azacyclic or azabicyclic group.   
     
     
       2. A compound as claimed in claim 1 wherein R 6  is an optionally substituted aromatic or non-aromatic azacyclic or azabicyclic group and Z is a --(CH 2 ) q  -group. 
     
     
       3. A compound as claimed in claim 1 wherein R 3  is H, X and Y together represent ═O and the double bond is absent. 
     
     
       4. A compound as claimed in claim 1 wherein Q 1  is an 3-indolyl group. 
     
     
       5. A compound as claimed in claim 1 wherein R 1  is H and Z is O, NH or NCH 3 . 
     
     
       6. A compound as claimed in claim 1 wherein R 4  is 3,5-bis(trifluoromethyl)phenyl. 
     
     
       7. A compound as claimed in claim 1 wherein q is 0, 1 or 2 and R 6  is 3-pyridyl, 4-pyridyl, quinuclidinyl or methylquinuclidinyl. 
     
     
       8. A compound which is: 5-(3,5-(bistrifluoromethyl)phenyl)-1-(3-indolyl)-2-(4-pyridylmethoxycarbonylamino)-3-pentanone;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(3-pyridylmethoxycarbonylamino)-3-pentanone;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(4-pyridylmethylureido)-3-pentanone hydrochloride;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(3-(4-quinuclidinyl)ureido)-3-pentanone hydrochloride;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(3(4-(1-methyl)quinuclidinyl)ureido)-3-pentanone iodide;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(3-(4-(1-ethyl)quinuclidinyl)ureido)-3-pentanone bromide;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(4-(1-methyl)piperidinyl)oxycarbonylamino)-3-pentanone hydrochloride;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(3-(4-(1-benzyl)piperidinyl)ureido)-3-pentanone;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(4-quinuclidinyl)oxycarbonylamino)-3-pentanone hydrochloride;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(3-methyl-3-(dimethylaminoethyl)ureido)-3-pentanone;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(3-methyl-3-(dimethylaminopropyl)ureido)-3-pentanone;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(dimethylaminopropyloxycarbonylamino)-3-pentanone;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-((2-pyridyl)ethoxycarbonylamino)-3-pentanone;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(3-methyl-3-(2-(4-pyridyl)ethyl)ureido)-3-pentanone;   5-(3,5-bis(trifluoromethyl)phenyl)-1-(3-indolyl)-2-(3-(4-(1-(2-chloro)ethyl)quinuclidinyl)ureido-3-pentanone chloride; or a pharmaceutically acceptable salt thereof.     
     
     
       9. A pharmaceutical composition which comprises a compound as claimed in claim 1 and a pharmaceutically acceptable carrier thereof. 
     
     
       10. A method of treatment of a clinical condition caused by the presence of an excess of tachykinin which comprises administering to the patient in need thereof an effective amount of a compound as claimed in claim 1. 
     
     
       11. The method of claim 10 wherein said clinical condition is selected from pain, inflammation, migraine or emesis.